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Adaptive regulation of neuronal excitability by a voltage- independent potassium conductance

Abstract

Many neurons receive a continuous, or ‘tonic’, synaptic input, which increases their membrane conductance, and so modifies the spatial and temporal integration of excitatory signals1,2,3. In cerebellar granule cells, although the frequency of inhibitory synaptic currents is relatively low, the spillover of synaptically released GABA (γ-aminobutyric acid)4 gives rise to a persistent conductance mediated by the GABA A receptor5,6,7 that also modifies the excitability of granule cells8. Here we show that this tonic conductance is absent in granule cells that lack the α6 and δ-subunits of the GABAA receptor. The response of these granule cells to excitatory synaptic input remains unaltered, owing to an increase in a ‘leak’ conductance, which is present at rest, with properties characteristic of the two-pore-domain K+ channel TASK-1 (refs 9,10,11,12). Our results highlight the importance of tonic inhibition mediated by GABAA receptors, loss of which triggers a form of homeostatic plasticity leading to a change in the magnitude of a voltage-independent K+ conductance that maintains normal neuronal behaviour.

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Figure 1: Absence of GGABA in α6-/- GCs.
Figure 2: GABAA receptors and GC excitability.
Figure 3: Increased K+ leak conductance in α6-/- GCs.
Figure 4: 2 -PK expression and development of GC leak conductance.

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References

  1. Bernander, O., Douglas, R. J., Martin, K. A. & Koch, C. Synaptic background activity influences spatiotemporal integration in single pyramidal cells. Proc. Natl Acad. Sci. USA 88, 11569–11573 (1991).

    Article  ADS  CAS  Google Scholar 

  2. Salin, P. A. & Prince, D. A. Spontaneous GABAA receptor-mediated inhibitory currents in adult rat somatosensory cortex. J. Neurophysiol. 75, 1573–1588 ( 1996).

    Article  CAS  Google Scholar 

  3. Häusser, M. & Clark, B. A. Tonic synaptic inhibition modulates neuronal output pattern and spatiotemporal synaptic integration. Neuron 19, 665–678 (1997).

    Article  Google Scholar 

  4. Rossi, D. J. & Hamann, M. Spillover-mediated transmission at inhibitory synapses promoted by high affinity α6 subunit GABAA receptors and glomerular geometry. Neuron 20 , 783–795 (1998).

    Article  CAS  Google Scholar 

  5. Kaneda, M., Farrant, M. & Cull-Candy, S. G. Whole-cell and single-channel currents activated by GABA and glycine in granule cells of the rat cerebellum. J. Physiol. (Lond.) 485, 419–435 (1995).

    Article  CAS  Google Scholar 

  6. Tia, S., Wang, J. F., Kotchabhakdi, N. & Vicini, S. Developmental changes of inhibitory synaptic currents in cerebellar granule neurons: role of GABAA receptor α6 subunit. J. Neurosci. 16, 3630–3640 (1996).

    Article  CAS  Google Scholar 

  7. Wall, M. J. & Usowicz, M. M. Development of action potential-dependent and independent spontaneous GABAA receptor-mediated currents in granule cells of postnatal rat cerebellum. Eur. J. Neurosci. 9, 533–548 (1997).

    Article  CAS  Google Scholar 

  8. Brickley, S. G., Cull-Candy, S. G. & Farrant, M. Development of a tonic form of synaptic inhibition in rat cerebellar granule cells resulting from persistent activation of GABA A receptors. J. Physiol. (Lond.) 497, 753–759 (1996).

    Article  CAS  Google Scholar 

  9. Duprat, F. et al. TASK, a human background K+ channel to sense external pH variations near physiological pH. EMBO J. 16, 5464–5471 (1997).

    Article  CAS  Google Scholar 

  10. Lesage, F. et al. TWIK-1, a ubiquitous human weakly inward rectifying K+ channel with a novel structure. EMBO J. 15 , 1004–1011 (1996).

    Article  CAS  Google Scholar 

  11. Millar, J. A. et al. A functional role for the two-pore domain potassium channel TASK-1 in cerebellar granule neurons. Proc. Natl Acad. Sci. USA 97, 3614–3618 ( 2000).

    Article  ADS  CAS  Google Scholar 

  12. Talley, E. M., Lei, Q., Sirois, J. E. & Bayliss, D. A. TASK-1, a two-pore domain K+ channel, is modulated by multiple neurotransmitters in motoneurons. Neuron 25, 399– 410 (2000).

    Article  CAS  Google Scholar 

  13. Eccles, J. C., Llinas, R. & Sasaki, K. The mossy fibre-granule cell relay of the cerebellum and its inhibitory control by Golgi cells. Exp. Brain Res. 1, 82–101 (1966).

    CAS  PubMed  Google Scholar 

  14. Maex, R. & De Schutter, E. Synchronization of golgi and granule cell firing in a detailed network model of the cerebellar granule cell layer. J. Neurophysiol. 80, 2521– 2537 (1998).

    Article  CAS  Google Scholar 

  15. Watanabe, D. et al. Ablation of cerebellar Golgi cells disrupts synaptic integration involving GABA inhibition and NMDA receptor activation in motor coordination. Cell 95, 17–27 (1998).

    Article  CAS  Google Scholar 

  16. Saxena, N. C. & Macdonald, R. L. Properties of putative cerebellar γ-aminobutyric acid A receptor isoforms. Mol. Pharmacol. 49, 567–579 (1996).

    CAS  PubMed  Google Scholar 

  17. Nusser, Z., Sieghart, W. & Somogyi, P. Segregation of different GABAA receptors to synaptic and extrasynaptic membranes of cerebellar granule cells. J. Neurosci. 18, 1693–703 (1998).

    Article  CAS  Google Scholar 

  18. Sassoe-Pognetto, M., Panzanelli, P., Sieghart, W. & Fritschy, J.-M. Colocalization of multiple GABAA receptor subtypes with gephyrin at postsynaptic sites. J. Comp. Neurol. 420, 481–498 (2000).

    Article  CAS  Google Scholar 

  19. Jones, A. et al. Ligand-gated ion channel subunit partnerships: GABAA receptor α6 subunit gene inactivation inhibits δ subunit expression. J. Neurosci. 17, 1350– 1362 (1997).

    Article  CAS  Google Scholar 

  20. Nusser, Z. et al. Alterations in the expression of GABAA receptor subunits in cerebellar granule cells after the disruption of the α6 subunit gene. Eur. J. Neurosci. 11, 1685 –1697 (1999).

    Article  CAS  Google Scholar 

  21. Homanics, G. E. et al. Gene knockout of the α6 subunit of the γ-aminobutyric acid type A receptor: lack of effect on responses to ethanol, pentobarbital, and general anesthetics. Mol. Pharmacol. 51, 588–596 (1997).

    Article  CAS  Google Scholar 

  22. Korpi, E. R. et al. Cerebellar granule-cell-specific GABAA receptors attenuate benzodiazepine-induced ataxia: evidence from α6-subunit-deficient mice. Eur. J. Neurosci. 11, 233– 240 (1999).

    Article  CAS  Google Scholar 

  23. Watkins, C. S. & Mathie, A. A non-inactivating K+ current sensitive to muscarinic receptor activation in rat cultured cerebellar granule neurons. J. Physiol. (Lond.) 491, 401–412 (1996).

    Article  CAS  Google Scholar 

  24. Leonoudakis, D. et al. An open rectifier potassium channel with two pore domains in tandem cloned from rat cerebellum. J. Neurosci. 18, 868–877 (1998).

    Article  CAS  Google Scholar 

  25. Fink, M. et al. A neuronal two P domain K+ channel stimulated by arachidonic acid and polyunsaturated fatty acids. EMBO J. 17, 3297–3308 (1998).

    Article  CAS  Google Scholar 

  26. Kim, Y., Bang, H. & Kim, D. TASK-3, a new member of the tandem pore K+ channel family. J. Biol. Chem. 275, 9340– 9347 (2000).

    Article  CAS  Google Scholar 

  27. Lopes, C. M., Gallagher, P. G., Buck, M. E., Butler, M. H. & Goldstein, S. A. Proton block and voltage gating are potassium-dependent in the cardiac leak channel Kcnk3. J. Biol. Chem. 275, 16969–16978 ( 2000).

    Article  CAS  Google Scholar 

  28. Desai, N. S., Rutherford, L. C. & Turrigiano, G. G. Plasticity in the intrinsic excitability of cortical pyramidal neurons. Nature Neurosci. 2, 515 –520 (1999).

    Article  CAS  Google Scholar 

  29. Turrigiano, G., Abbott, L. F. & Marder, E. Activity-dependent changes in the intrinsic properties of cultured neurons. Science 264, 974– 977 (1994).

    Article  ADS  CAS  Google Scholar 

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Acknowledgements

Supported by a Wellcome Trust Programme grant to S.G.C.-C. and a Human Frontier Science Program grant to W.W. We thank L. Cathala, B. Clark, M. Häusser, S.-Q. Liu, T. Takahashi and D. Wyllie for comments on the manuscript, and A. Mathie and B. Robertson for valuable discussion.

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Correspondence to Mark Farrant.

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Brickley, S., Revilla, V., Cull-Candy, S. et al. Adaptive regulation of neuronal excitability by a voltage- independent potassium conductance. Nature 409, 88–92 (2001). https://doi.org/10.1038/35051086

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